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Identification of a potential “hotspot” DNA region in the RUNX1 gene targeted by mitoxantrone in therapy‐related acute myeloid leukemia with t(16;21) translocation
Author(s) -
Ottone Tiziana,
Hasan Syed Khizer,
Montefusco Enrico,
Curzi Paola,
Mays Ashley N.,
Chessa Luciana,
Ferrari Antonella,
Conte Esmeralda,
Noguera Nelida Inés,
Lavorgna Serena,
Ammatuna Emanuele,
Divona Mariadomenica,
Bovetti Katia,
Amadori Sergio,
Grimwade David,
LoCoco Francesco
Publication year - 2009
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20633
Subject(s) - chromosomal translocation , mitoxantrone , myeloid leukemia , biology , runx1 , leukemia , fusion gene , cancer research , microbiology and biotechnology , gene , genetics , chemotherapy , transcription factor
The translocation t(16;21) involving RUNX1 ( AML1 ) and resulting in the RUNX1‐CBFA2T3 fusion is a rare but recurrent abnormality mostly found in therapy‐related acute myeloid leukemia (t‐AML) associated with agents targeting topoisomerase II (topo II). We characterized, at the genomic level, the t(16;21) translocation in a patient who developed t‐AML after treatment of multiple sclerosis with mitoxantrone (MTZ). Long template nested PCR of genomic DNA followed by direct sequencing enabled the localization of RUNX1 and CBFA2T3 ( ETO2 ) breakpoints in introns 5 and 3, respectively. Sequencing of the cDNA with specific primers showed the presence of the expected RUNX1‐CBFA2T3 fusion transcript in leukemic cells. The RUNX1 intron 5 breakpoint was located at nucleotide position 24,785. This region contained an ATGCCCCAG nucleotide sequence showing ∼90% homology to a “hotspot” DNA region ATGCCCTAG present in intron 6 of PML previously identified in therapy‐related acute promyelocytic leukemia cases arising following treatment with MTZ. This study suggests a wider distribution in the human genome, and particularly at genes involved in chromosome translocations observed in t‐AML, of DNA regions (hotspot) targeted by specific topo II drugs. © 2008 Wiley‐Liss, Inc.